The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
A common starting point in drug development is the identification through screening or rational design of compounds that bind or exhibit some inhibitory activity against their intended targets. Because of the theoretically large chemical space of drug-like compounds, the “hit rate” of such approaches can be relatively low. In addition, many “hits” bind to the intended drug target with lower affinities than useful. Often, the lead compounds identified bind to their targets with micromolar and sometimes weaker affinities. To become effective drugs, the binding affinities of those compounds need to be optimized by three or more orders of magnitude. As a consequence, more effort has to be spent on optimization to obtain lead compounds with an acceptable affinity.
This task is not a trivial one if one considers that it may have to be done while satisfying several other stringent constraints, e.g., the molecular mass cannot substantially exceed 500 Da in order for the molecule to be orally bioavailable; the compound should exhibit appropriate target selectivity, appropriate membrane permeability and sufficient water solubility; the compound should exhibit an adequate pharmacokinetic profile, no toxicity, and so forth. These constraints considerably reduce the universe of chemical functionalities that can be utilized to achieve the optimization goals. The result is often that low affinity lead compounds having unique properties become abandoned during the drug development process.
These affinity limitations are not unique to small molecule drug compounds. Many of the antibody-based drugs presently used in clinically exhibit affinities in the nanomolar to picomolar range; however, the combinatorial phage display methods used to generate lead compounds often rely on naive immunoglobulin libraries which lack the high affinity binders typically arising from antigen stimulation. The result is typically an antibody lead compound which requires rounds of affinity maturation in order to arrive at a successful drug.
As noted above, lead optimization strategies often result in the loss of promising drug candidates and high failure rates in drug discovery programs. There remains a need in the art for approaches to improving success rates in drug discovery.